Cellular mechanisms of MYO7A in the retina

About This Grant

PROJECT SUMMARY / ABSTRACT Proposed experiments in this multiple-PI application address the retinal functions of MYO7A, which when mutated causes Usher syndrome 1B. Individuals with USH1B are congenitally deaf, have vestibular deficiencies, and develop progressive photoceptor degeneration. Previous studies have focused on the hearing and vestibular phenotypes of USH1B, as these are modeled by the mouse Myo7A knock-out. The knock-out mice also show Retinal Pigment Epithelium (RPE) dysfunction including defects in melanosome motility and localization, as well as impaired phagocytosis of photoreceptor outer segments. It also has a photoreceptor phenotype but does not develop photoreceptor degeneration. Here we provide novel observations that RPE in multiple species show severe cell junction abnormalities. We also show evidence that myo7ab mutations in zebrafish not only have RPE defects, but also develop progressive photoreceptor degeneration. Thus, we define the first experimental model of USH1B to model vision loss. A third important observation is that retinal MYO7A in both mammals and zebrafish express splice variants that affect the MyTH4-FERM domain, a well characterized cargo binding domain of the actin-based motor protein. Leveraging the complimentary expertises of the two PIs, as well as multiple complimentary experimental models (USH1B patient derived RPE cells, Myo7a-mutant mice and pigs, and myo7ab zebrafish mutants), two Aims address the mechanisms underlying cell junction dysfunction, the role of each MYO7A isoform, and the ability of either MyTH4-FERM variant to prevent USH1B pathologies, including photoreceptor loss, when they are re-expressed in relevant retinal cell types. Findings from this project will provide fundamental knowledge of basic cellular functions of MYO7A, and its variants expressed within the retina, including potential cell- autonomous and non-cell-autonomous roles in photoreceptor health. From a clinical relevance perspective, results can shape future gene augmentation therapies, including what are the important MYO7A isoforms and what are the critical cell types to target in order to slow or prevent photoreceptor degeneration.